Combining non-invasive liquid biopsy and a methylation analysis to assess surgical risk for early esophageal cancer.

Background: While the widespread use of endoscopic submucosal dissection (ESD) has significantly reduced the incidence of early esophageal cancer (ESCA), the limited ability of ESD to strip deep infiltrating esophageal lesions results in a considerable risk of intraoperative perforation. Circulating-free DNA (cfDNA) is widely used in modern tumor screening due to its non-invasive detection capabilities. A methylation analysis offers vital insights into the condition and advancement of malignancies due to its unique positioning, such as a marker of cancer. This study investigated the potential of combining a non-invasive liquid biopsy technique, along with a methylation analysis, to assess the surgical perforation risk of ESCA patients. Methods: In this study, we conducted an analysis of gene expression differences between stage I esophageal squamous carcinoma samples and healthy tissue samples using data from The Cancer Genome Atlas (TCGA) database. We also identified the genes associated with progression-free survival (PFS) in esophageal squamous carcinoma. Integrating the framework of the methylation analysis, we explored the methylated sites of these distinct genes. To refine this process, we used the Shiny Methylation Analysis Resource Tool (SMART) to conduct a comprehensive analysis of these sites. We then confirmed the stability of the methylation sites in different lesion conditions using methylation-specific quantitative polymerase chain reaction (MS-qPCR) with paraffin tissue samples collected after ESD. Results: We analyzed RNA-sequencing data from 42 early stage ESCA patients and 17 controls, identifying 1,263 up-regulated and 460 down-regulated genes. Functional analyses revealed involvement in key pathways such as cell cycle regulation and immune responses. Furthermore, we identified 38 differentially expressed genes associated with PFS. Using SMART analysis, we found 217 hyper-methylated regions in 38 genes, suggesting potential early markers for ESCA. Validation experiments confirmed the reliability of 29 hyper-methylated regions in FFPE tissue samples and 6 regions in cfDNA. A LunaCAM model showed high accuracy [area under the curve (AUC) =0.89] in discriminating early ESCA. Integrated assessment of six highly methylated regions significantly improved predictive performance, with 90.56% sensitivity, highlighting the importance of combinatorial biomarker evaluation for early cancer detection. Conclusions: This study established a novel approach that integrates non-invasive testing with a methylation analysis to assess the surgical risk of early ESCA patients. The significance of changes in methylation sites in relation to lesion status should not be underestimated, as they have the potential to offer vital insights for proactive risk assessments before surgery.

Side-specific factors for intraoperative hemodynamic instability in laparoscopic adrenalectomy for pheochromocytoma: a comparative study.

BACKGROUND: Adrenalectomy for pheochromocytoma (PHEO) is challenging because of the high risk of intraoperative hemodynamic instability (HDI). This study aimed to compare the incidence and risk factors of intraoperative HDI between laparoscopic left adrenalectomy (LLA) and laparoscopic right adrenalectomy (LRA). METHODS: We retrospectively analyzed two hundred and seventy-one patients aged > 18 years with unilateral benign PHEO of any size who underwent transperitoneal laparoscopic adrenalectomy at our hospitals between September 2016 and September 2023. Patients were divided into LRA (N = 122) and LLA (N = 149) groups. Univariate and multivariate logistic regression analyses were used to predict intraoperative HDI. In multivariate analysis for the prediction of HDI, right-sided PHEO, PHEO size, preoperative comorbidities, and preoperative systolic blood pressure were included. RESULTS: Intraoperative HDI was significantly higher in the LRA group than in the LLA (27% vs. 9.4%, p < 0.001). In the multivariate regression analysis, right-sided tumours showed a higher risk of intraoperative HDI (odds ratio [OR] 5.625, 95% confidence interval [CI], 1.147-27.577, p = 0.033). The tumor size (OR 11.019, 95% CI 3.996-30.38, p < 0.001), presence of preoperative comorbidities [diabetes mellitus, hypertension, and coronary heart disease] (OR 7.918, 95% CI 1.323-47.412, p = 0.023), and preoperative systolic blood pressure (OR 1.265, 95% CI 1.07-1.495, p = 0.006) were associated with a higher risk of HDI in both LRA and LLA, with no superiority of one side over the other. CONCLUSION: LRA was associated with a significantly higher intraoperative HDI than LLA. Right-sided PHEO was a risk factor for intraoperative HDI.

Is previous radical prostatectomy a contraindication to minimally invasive inguinal hernia repair? A contemporary meta-analysis.

INTRODUCTION: Traditionally, radical prostatectomy (RP) has been considered a contraindication to minimally invasive inguinal hernia repair. Purpose of this systematic review was to examine the current evidence and outcomes of minimally invasive inguinal hernia repair after RP. MATERIALS AND METHODS: Web of Science, PubMed, and EMBASE data sets were consulted. Laparoscopic transabdominal preperitoneal repair (TAPP), robotic TAPP (r-TAPP), and totally extraperitoneal (TEP) repair were included. RESULTS: Overall, 4655 patients (16 studies) undergoing TAPP, r-TAPP, and TEP inguinal hernia repair after RP were included. The age of the patients ranged from 35 to 85 years. Open (49.1%), laparoscopic (7.4%), and robotic (43.5%) RP were described. Primary unilateral hernia repair was detailed in 96.3% of patients while 2.8% of patients were operated for recurrence. The pooled prevalence of intraoperative complication was 0.7% (95% CI 0.2-3.4%). Bladder injury and epigastric vessels bleeding were reported. The pooled prevalence of conversion to open was 0.8% (95% CI 0.3-1.7%). The estimated pooled prevalence of seroma, hematoma, and surgical site infection was 3.2% (95% CI 1.9-5.9%), 1.7% (95% CI 0.9-3.1%), and 0.3% (95% CI = 0.1-0.9%), respectively. The median follow-up was 18 months (range 8-48). The pooled prevalence of hernia recurrence and chronic pain were 1.1% (95% CI 0.1-3.1%) and 1.9% (95% CI 0.9-4.1%), respectively. CONCLUSIONS: Minimally invasive inguinal hernia repair seems feasible, safe, and effective for the treatment of inguinal hernia after RP. Prostatectomy should not be necessarily considered a contraindication to minimally invasive inguinal hernia repair.

Does Thoracic Duct Ligation at the Time of Esophagectomy Impact Long-Term Survival? An Individual Patient Data Meta-Analysis.

Background: Thoracic duct ligation (TDL) during esophagectomy has been proposed to reduce the risk of postoperative chylothorax. Because of its role in immunoregulation, some authors argued that it had an unfavorable TDL effect on survival. The aim of this study was to analyze the effect of TDL on overall survival (OS). Methods: PubMed, MEDLINE, Scopus, and Web of Science were searched through December 2023. The primary outcome was 5-year OS. The restricted mean survival time difference (RMSTD), hazard ratios (HRs), and 95% confidence intervals (CI) were used as pooled effect size measures. The GRADE methodology was used to summarize the certainty of the evidence. Results: Five studies (3291 patients) were included. TDL was reported in 54% patients. The patients' age ranged from 49 to 69, 76% were males, and BMI ranged from 18 to 26. At the 5-year follow-up, the combined effect from the multivariate meta-analysis is -3.5 months (95% CI -6.1, -0.8) indicating that patients undergoing TDL lived 3.5 months less compared to those without TDL. TDL was associated with a significantly higher hazard for mortality at 12 months (HR 1.54, 95% CI 1.38-1.73), 24 months (HR 1.21, 95% CI 1.12-1.35), and 28 months (HR 1.14, 95% CI 1.02-1.28). TDL and noTDL seem comparable in terms of the postoperative risk for chylothorax (RR = 0.66; p = 0.35). Conclusions: In this study, concurrent TDL was associated with reduced 5-year OS after esophagectomy. This may suggest the need of a rigorous follow-up within the first two years of follow-up.

Short-Term Outcomes Analysis Comparing Open, Laparoscopic, Laparoscopic-Assisted, and Robotic Distal Gastrectomy for Locally Advanced Gastric Cancer: A Randomized Trials Network Analysis.

BACKGROUND: Minimally invasive surgery for the treatment of locally advanced gastric cancer (AGC) is debated. The aim of this study was to execute a comprehensive assessment of principal surgical treatments for resectable distal gastric cancer. METHODS: Systematic review and randomized controlled trials (RCTs) network meta-analysis. Open (Op-DG), laparoscopic-assisted (LapAs-DG), totally laparoscopic (Lap-DG), and robotic distal gastrectomy (Rob-DG) were compared. Pooled effect-size measures were the risk ratio (RR), the weighted mean difference (WMD), and the 95% credible intervals (CrIs). RESULTS: Ten RCTs (3823 patients) were included. Overall, 1012 (26.5%) underwent Lap-DG, 902 (23.6%) LapAs-DG, 1768 (46.2%) Op-DG, and 141 (3.7%) Rob-DG. Anastomotic leak, severe complications (Clavien-Dindo > 3), and in-hospital mortality were comparable. No differences were observed for reoperation rate, pulmonary complications, postoperative bleeding requiring transfusion, surgical-site infection, cardiovascular complications, number of harvested lymph nodes, and tumor-free resection margins. Compared to Op-DG, Lap-DG and LapAs-DG showed a significantly reduced intraoperative blood loss with a trend toward shorter time to first flatus and reduced length of stay. CONCLUSIONS: LapAs-DG, Lap-DG, and Rob-DG performed in referral centers by dedicated surgeons have comparable short-term outcomes to Op-DG for locally AGC.

Long-Term Impact of Severe Postoperative Complications after Esophagectomy for Cancer: Individual Patient Data Meta-Analysis.

BACKGROUND: Severe postoperative complications (SPCs) may occur after curative esophagectomy for cancer and are associated with prolonged hospital stay, augmented costs, and increased in-hospital mortality. However, the effect of SPCs on survival after esophagectomy is uncertain. AIM: To assess the impact of severe postoperative complications (SPCs) on long-term survival following curative esophagectomy for cancer, we conducted a systematic search of PubMed, MEDLINE, Scopus, and Web of Science databases up to December 2023. The included studies examined the relationship between SPCs and survival outcomes, defining SPCs as Clavien-Dindo grade > 3. The primary outcome measure was long-term overall survival (OS). We used restricted mean survival time difference (RMSTD) and 95% confidence intervals (CIs) to calculate pooled effect sizes. Additionally, we applied the GRADE methodology to evaluate the certainty of the evidence. RESULTS: Ten studies (2181 patients) were included. SPCs were reported in 651 (29.8%) patients. The RMSTD overall survival analysis shows that at 60-month follow-up, patients experiencing SPCs lived for 8.6 months (95% Cis -12.5, -4.7; p < 0.001) less, on average, compared with no-SPC patients. No differences were found for 60-month follow-up disease-free survival (-4.6 months, 95% CIs -11.9, 1.9; p = 0.17) and cancer-specific survival (-6.8 months, 95% CIs -11.9, 1.7; p = 0.21). The GRADE certainty of this evidence ranged from low to very low. CONCLUSIONS: This study suggests a statistically significant detrimental effect of SPCs on OS in patients undergoing curative esophagectomy for cancer. Also, a clinical trend toward reduced CSS and DFS was perceived.

Effect of complete mesocolic excision (cme) on long-term survival after right colectomy for cancer: multivariate meta-analysis and restricted mean survival time estimation.

INTRODUCTION: Debate exists concerning the impact of complete mesocolic excision (CME) on long-term oncological outcomes. The aim of this review was to condense the updated literature and assess the effect of CME on long-term survival after right colectomy for cancer. METHODS: PubMed, MEDLINE, Scopus, and Web of Science were searched through July 2023. The included studies evaluated the effect of CME on survival. The primary outcome was long-term overall survival. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures. GRADE methodology was used to summarize the certainty of evidence. RESULTS: Ten studies (3665 patients) were included. Overall, 1443 (39.4%) underwent CME. The RMSTD analysis shows that at 60-month follow-up, stage I-III CME patients lived 2.5 months (95% CI 1.1-4.1) more on average compared with noCME patients. Similarly, stage III patients that underwent CME lived longer compared to noCME patients at 55-month follow-up (6.1 months; 95% CI 3.4-8.5). The time-dependent HRs analysis for CME vs. noCME (stage I-III disease) shows a higher mortality hazard in patients with noCME at 6 months (HR 0.46, 95% CI 0.29-0.71), 12 months (HR 0.57, 95% CI 0.43-0.73), and 24 months (HR 0.73, 95% CI 0.57-0.92) up to 27 months. CONCLUSIONS: This study suggests that CME is associated with unclear OS benefit in stage I-III disease. Caution is recommended to avoid overestimation of the effect of CME in stage III disease since the marginal benefit of a more extended resection may have been influenced by tumor biology/molecular profile and multimodal adjuvant treatments.

Impact of pulmonary complications following esophagectomy on long-term survival: multivariate meta-analysis and restricted mean survival time assessment.

Pulmonary complications (PC) are common after esophagectomy and their impact on long-term survival is not defined yet. The present study aimed to assess the effect of postoperative PCs on long-term survival after esophagectomy for cancer. Systematic review of the literature through February 1, 2023, was performed. The included studies evaluated the effect of PC on long-term survival. Primary outcome was long-term overall survival (OS). Cancer-specific survival (CSS) and disease-free survival (DFS) were secondary outcomes. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures. Eleven studies were included (3423 patients). Overall, 674 (19.7%) patients developed PC. The RMSTD analysis shows that at 60-month follow-up, patients not experiencing PC live an average of 8.5 (95% CI 6.2-10.8; p < 0.001) months longer compared with those with PC. Similarly, patients not experiencing postoperative PC seem to have significantly longer CSS (8 months; 95% CI 3.7-12.3; p < 0.001) and DFS (5.4 months; 95% CI 1.6-9.1; p = 0.005). The time-dependent HRs analysis shows a reduced mortality hazard in patients without PC at 12 (HR 0.6, 95% CI 0.51-0.69), 24 (HR 0.64, 95% CI 0.55-0.73), 36 (HR 0.67, 95% CI 0.55-0.79), and 60 months (HR 0.69, 95% CI 0.51-0.89). This study suggests a moderate clinical impact of PC on long-term OS, CSS, and DFS after esophagectomy. Patients not experiencing PC seem to have a significantly reduced mortality hazard up to 5 years of follow-up.

Long-Term Impact of D2 Lymphadenectomy during Gastrectomy for Cancer: Individual Patient Data Meta-Analysis and Restricted Mean Survival Time Estimation.

BACKGROUND: Debate exists concerning the impact of D2 vs. D1 lymphadenectomy on long-term oncological outcomes after gastrectomy for cancer. METHODS: PubMed, MEDLINE, Scopus, and Web of Science were searched and randomized controlled trials (RCTs) analyzing the effect of D2 vs. D1 on survival were included. Overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) were assessed. Restricted mean survival time difference (RMSTD) and 95% confidence intervals (CI) were used as effect size measures. RESULTS: Five RCTs (1653 patients) were included. Overall, 805 (48.7%) underwent D2 lymphadenectomy. The RMSTD OS analysis shows that at 60-month follow-up, D2 patients lived 1.8 months (95% CI -4.2, 0.7; p = 0.14) longer on average compared to D1 patients. Similarly, 60-month CSS (1.2 months, 95% CI -3.9, 5.7; p = 0.72) and DFS (0.8 months, 95% CI -1.7, 3.4; p = 0.53) tended to be improved for D2 vs. D1 lymphadenectomy. CONCLUSIONS: Compared to D1, D2 lymphadenectomy is associated with a clinical trend toward improved OS, CSS, and DFS at 60-month follow-up.

Short-term Outcomes of Different Techniques for Gastric Ischemic Preconditioning Before Esophagectomy: A Network Meta-analysis.

BACKGROUND: Ischemia at the anastomotic site plays a critical role determinant in the development of anastomosis-related complications after esophagectomy. Gastric ischemic conditioning (GIC) before esophagectomy has been described to improve the vascular perfusion at the tip of the gastric conduit with a potential effect on anastomotic leak (AL) and stenosis (AS) risk minimization. Laparoscopic (LapGIC) and angioembolization (AngioGIC) techniques have been reported. PURPOSE: Compare short-term outcomes among different GIC techniques. MATERIALS AND METHODS: Systematic review and network meta-analysis. One-step esophagectomy (noGIC), LapGIC, and AngioGIC were compared. Primary outcomes were AL, AS, and gastric conduit necrosis (GCN). Risk ratio (RR) and weighted mean difference (WMD) were used as pooled effect size measures, whereas 95% credible intervals (CrIs) were used to assess relative inference. RESULTS: Overall, 1760 patients (14 studies) were included. Of those, 1028 patients (58.4%) underwent noGIC, 593 (33.6%) LapGIC, and 139 (8%) AngioGIC. AL was reduced for LapGIC versus noGIC (RR=0.68; 95% CrI 0.47-0.98) and AngioGIC versus noGIC (RR=0.52; 95% CrI 0.31-0.93). Similarly, AS was reduced for LapGIC versus noGIC (RR=0.32; 95% CrI 0.12-0.68) and AngioGIC versus noGIC (RR=1.30; 95% CrI 0.65-2.46). The indirect comparison, assessed with the network methodology, did not show any differences for LapGIC versus AngioGIC in terms of postoperative AL and AS risk. No differences were found for GCN, pulmonary complications, overall complications, hospital length of stay, and 30-day mortality among different treatments. CONCLUSIONS: Compared to noGIC, both LapGIC and AngioGIC before esophagectomy seem equivalent and associated with a reduced risk for postoperative AL and AS.

Safety profile of magnetic sphincter augmentation for gastroesophageal reflux disease.

Background: The magnetic sphincter augmentation (MSA) procedure is an effective treatment for gastroesophageal reflux disease (GERD). Adverse events requiring MSA device removal are rare, but the true prevalence and incidence may be underestimated. Methods: Retrospective study on a prospectively collected database. Patients who underwent MSA procedure between March 2007 and September 2021 in two tertiary-care referral centers for esophageal surgery were included. The trend of MSA explant, the changes in the sizing technique and crura repair over the years, the technique of explant, and the clinical outcomes of the revisional procedure were reviewed. Results: Out of 397 consecutive patients, 50 (12.4%) underwent MSA removal, with a median time to explant of 39.5 [IQR = 53.7] months. Main symptoms leading to removal were dysphagia (43.2%), heartburn (25%), and epigastric pain (13.6%). Erosion occurred in 2.5% of patients. Smaller (12- and 13-bead) devices were the ones most frequently explanted. The majority of the explants were performed laparoscopically with endoscopic assistance. There was no perioperative morbidity, and the median length of stay was 2.8 ± 1.4 days. After 2014, changes in sizing technique and crura repair resulted in a decreased incidence of explants from 23% to 5% (p < 0.0001). Multivariate analysis confirmed the protective role of added bead units [HR 0.06 (95% CI = 0.001-0.220); p < 0.000]. Conclusion: Oversizing and full mediastinal dissection with posterior hiatoplasty may improve the outcomes of the MSA procedure and possibly reduce removal rates.

Intraoperative endomanometric laparoscopic Nissen fundoplication improves postoperative outcomes in large sliding hiatus hernias with severe gastroesophageal reflux disease: a retrospective cohort study.

BACKGROUND: Laparoscopic Nissen fundoplication (LNF) is the gold standard surgical intervention for gastroesophageal reflux disease (GERD). LNF can be followed by recurrent symptoms or complications affecting patient satisfaction. The aim of this study is to assess the value of the intraoperative endomanometric evaluation of esophagogastric competence and pressure combined with LNF in patients with large sliding hiatus hernia (>5 cm) with severe GERD (DeMeester score >100). MATERIALS AND METHODS: This is a retrospective, multicenter cohort study. Baseline characteristics, postoperative dysphagia and gas bloat syndrome, recurrent symptoms, and satisfaction were collected from a prospectively maintained database. Outcomes analyzed included recurrent reflux symptoms, postoperative side effects, and satisfaction with surgery. RESULTS: Three hundred sixty patients were stratified into endomanometric LNF (180 patients, LNF+) and LNF alone (180 patients, LNF). Recurrent heartburn (3.9 vs. 8.3%) and recurrent regurgitation (2.2 vs. 5%) showed a lower incidence in the LNF+ group ( P =0.012). Postoperative score III recurrent heartburn and score III regurgitations occurred in 0 vs. 3.3% and 0 vs. 2.8% cases in the LNF+ and LNF groups, respectively ( P =0.005). Postoperative persistent dysphagia and gas bloat syndrome occurred in 1.75 vs. 5.6% and 0 vs. 3.9% of patients ( P =0.001). Score III postoperative persistent dysphagia was 0 vs. 2.8% in the two groups ( P =0.007). There was no redo surgery for dysphagia after LNF+. Patient satisfaction at the end of the study was 93.3 vs. 86.7% in both cohorts, respectively ( P =0.05). CONCLUSIONS: Intraoperative high-resolution manometry and endoscopic were feasible in all patients, and the outcomes were favorable from an effectiveness and safety standpoint.

Effect of gastric ischemic conditioning prior to esophagectomy: systematic review and meta-analysis.

Ischemia at the anastomotic site is thought to be a protagonist in the development of anastomosis-related complications while different strategies to overcome this problem have been reported. Gastric ischemic conditioning (GIC) prior to esophagectomy has been described with this intent. Evaluate the effect of GIC on anastomotic complications after esophagectomy. Scopus, Web of Science, MEDLINE, and PubMed were investigated up to March 31st, 2023. We considered articles that appraised short-term outcomes after GIC vs. no GIC in patients undergoing esophagectomy. Anastomotic leak (AL), anastomotic stricture (AS), and gastric conduit necrosis (GCN) were primary outcomes. Risk ratio (RR) and standardized mean difference (SMD) were used as pooled effect size measures, whereas 95% confidence intervals (95% CIs) were used to calculate related inference. Fourteen studies (1760 patients) were included. Of those, 732 (41.6%) underwent GIC, while 1028 (58.4%) underwent one-step esophagectomy. Compared with no GIC, GIC was related to a reduced RR for AL (R RR = 0.63; 95% CI 0.47-0.86; p < 0.01) and AS (RR = 0.51; 95% CI 0.29-0.91; p = 0.02), whereas no differences were found for GCN (RR = 0.56; 95% CI 0.19-1.61; p = 0.28). Postoperative pneumonia (RR = 1.09; p = 0.99), overall complications (RR = 0.87; p = 0.19), operative time (SMD - 0.58; p = 0.07), hospital stay (SMD 0.66; p = 0.09), and 30-day mortality (RR = 0.69; p = 0.22) were comparable. GIC prior to esophagectomy seems associated with a reduced risk for AL and AS. Further studies are necessary to identify the subset of patients who can benefit from this procedure, the optimal technique, and the timing of GIC prior to esophagectomy.